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Original ArticleBrief ReportFree Preview

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

List of authors.
  • Jinkuk Kim, Ph.D.,
  • Chunguang Hu, M.D., Ph.D.,
  • Christelle Moufawad El Achkar, M.D.,
  • Lauren E. Black, Ph.D.,
  • Julie Douville, Ph.D.,
  • Austin Larson, M.D.,
  • Mary K. Pendergast, J.D.,
  • Sara F. Goldkind, M.D.,
  • Eunjung A. Lee, Ph.D.,
  • Ashley Kuniholm, B.S.,
  • Aubrie Soucy, B.A.,
  • Jai Vaze, B.A.,
  • Nandkishore R. Belur, M.S.,
  • Kristina Fredriksen, B.S.,
  • Iva Stojkovska, B.S.,
  • Alla Tsytsykova, Ph.D.,
  • Myriam Armant, Ph.D.,
  • Renata L. DiDonato, B.S.,
  • Jaejoon Choi, Ph.D.,
  • Laura Cornelissen, Ph.D.,
  • Luis M. Pereira, Ph.D.,
  • Erika F. Augustine, M.D.,
  • Casie A. Genetti, M.S.,
  • Kira Dies, Sc.M.,
  • Brenda Barton, R.N.,
  • Lucinda Williams, D.N.P.,
  • Benjamin D. Goodlett, Ph.D.,
  • Bobbie L. Riley, M.D.,
  • Amy Pasternak, D.P.T., P.C.S.,
  • Emily R. Berry, D.P.T.,
  • Kelly A. Pflock, D.P.T., P.C.S.,
  • Stephen Chu, Pharm.D.,
  • Chantal Reed, Ph.D.,
  • Kimberly Tyndall, B.A.,
  • Pankaj B. Agrawal, M.B., B.S., M.M.Sc.,
  • Alan H. Beggs, Ph.D.,
  • P. Ellen Grant, M.D.,
  • David K. Urion, M.D.,
  • Richard O. Snyder, Ph.D.,
  • Susan E. Waisbren, Ph.D.,
  • Annapurna Poduri, M.D., M.P.H.,
  • Peter J. Park, Ph.D.,
  • Al Patterson, Pharm.D.,
  • Alessandra Biffi, M.D.,
  • Joseph R. Mazzulli, Ph.D.,
  • Olaf Bodamer, M.D., Ph.D.,
  • Charles B. Berde, M.D., Ph.D.,
  • and Timothy W. Yu, M.D., Ph.D.

Summary

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an “N-of-1” study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila’s Miracle Foundation and others.)

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Funding and Disclosures

Supported by Mila’s Miracle Foundation, Boston Children’s Hospital, the Harvard Catalyst Clinical and Translational Research Center (through National Center for Advancing Translational Sciences grant 8UL1TR000170), the Mooney Family Fund, and the Boston Children’s Hospital Translational Research Program. Claritas Genomics and WuXi NextCODE provided whole-genome sequencing and Clinical Laboratory Improvement Amendments confirmation. The process of obtaining consent, the enrollment of patients, and molecular genetic analyses were conducted with the assistance and support of the Manton Center for Orphan Disease Research and the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (IDDRC) Molecular Genetics Core Laboratory, which is supported in part by a grant from the National Institutes of Health (1U54HD090255).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Kim and Hu contributed equally to this article.

This article was published on October 9, 2019, at NEJM.org.

We thank the members of our patient’s family for their participation, trust, and partnership, and the many people who contributed their time, advice, and expertise to this project, including Firoz Antia, Frank Bennett, Daniel Capaldi, Mary Ellen Cortizas, Alan Crane, Basil Darras, Tony DeFusco, Craig Dobbs, Diana H. Chin, Didem Demirbas Cakici, Cynthia Gubbels, Luc Chouinard, Richard Finkel, Jim Gombold, Jeff Gulcher, Liz Groebel, Damian Ackermann, Scott Henry, Carl Hull, Cameron Jones, Susan Kornetsky, Art Krieg, Ron Lacro, Helen Legakis, Paul McLean, Steve Miklasz, Patrice Milos, Myriam Mirza, Max Moore, Roger O’Rielly, Philip Reilly, Audrey Saumure Di Fruscia, Susan Srivatsa, Jessica Stewart, John Thompson, Lloyd Tilman, Andy Vick, Hong Vu and colleagues in the Division of Gastroenterology and Inborn Errors Products from the Center for Drug Evaluation and Research at the Food and Drug Administration, Josh Whisenand, David Williams, Fran Wincott, and Michael Wourms.

Author Affiliations

From the Divisions of Genetics and Genomics (J.K., C.H., E.A.L., A.S., J.V., R.L.D., J.C., P.B.A., A.H.B., S.E.W., O.B., T.W.Y.), Newborn Medicine (P.B.A., P.E.G.), and Neuroradiology (P.E.G.), the Departments of Neurology (C.M.E.A., D.K.U., A. Poduri), Anesthesiology, Critical Care and Pain Medicine (L.C., C.B.B.), Physical and Occupational Therapy (A. Pasternak, E.R.B., K.A.P.), and Pharmacy (S.C., A. Patterson), the Institutional Centers for Clinical and Translational Research (A.K., B.B., L.W.), and the Manton Center for Orphan Disease Research (C.A.G., P.B.A., A.H.B.), Boston Children’s Hospital (A.K., A.T., M.A., L.M.P., K.D., B.B., L.W., B.D.G., B.L.R., A.B.), the Department of Biomedical Informatics (J.K., P.J.P.), Harvard Medical School (J.K., C.M.E.A., E.A.L., L.C., B.D.G., B.L.R., P.B.A., A.H.B., P.E.G., D.K.U., S.E.W., P.J.P., A. Patterson, A.B., O.B., C.B.B., T.W.Y.), and the Gene Therapy Program (A.B.), Boston Children’s and Dana–Farber Cancer and Blood Disorders Center (A.K., B.B., L.W.), Boston, Charles River Laboratories, Wilmington (L.E.B.), and Broad Institute of MIT and Harvard (E.A.L., O.B., T.W.Y.), Cambridge — all in Massachusetts; Charles River Laboratories, Montreal (J.D.); University of Colorado School of Medicine, Aurora (A.L.); Pendergast Consulting, Washington, DC (M.K.P.); Goldkind Consulting, Potomac, MD (S.F.G.); the Department of Neurology Feinberg School of Medicine, Northwestern University, Chicago (N.R.B., K.F., I.S., J.R.M.); the Department of Neurology, University of Rochester Medical Center, Rochester, NY (E.F.A.); Brain Hz Consulting, Del Mar, CA (C.R.); Tyndall Consulting, Wake Forest, NC (K.T.); and Brammer Bio, Alachua, FL (R.O.S.).

Address reprint requests to Dr. Yu at the Division of Genetics and Genomics, Boston Children’s Hospital, 300 Longwood Ave., Mailstop BCH3150, Boston, MA 02115, or at .

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